The hypothalamus critically controls body weight and energy homeostasis. The Insulin and leptin pathways are most pivotal in the hypothalamic regulation of energy balance and therefore critical in the prevention against excessive energy accumulation and the associated obesity and type 2 diabetes (T2D). Recent advances show that persistent overnutrition induces hypothalamic insensitivity to insulin and leptin; however, the involved molecular basis remains unclear. Following our previous discovery that pro-inflammatory nuclear transcription factor NF-&#954;B and its upstream activator IKK&#946; are activated in peripheral tissues by overnutrition leading to local insulin resistance, this proposal will investigate the role of IKK&#946;/NF-&#954;B in the hypothalamic dysregulation of energy balance, and in particular, in relation to the loss of insulin and leptin sensitivity in the hypothalamus. Preliminary results show that a high-fat diet activates IKK&#946;/NF-&#954;B in mouse hypothalamus, while activation of IKK&#946;/NF-&#954;B induces hypothalamic insulin resistance. Animal tests further show that activation of IKK&#946;/NF-&#954;B in the mediobasal hypothalamus (MBH) induced weight gain, while the ablation of IKK&#946; in a subtype of insulin/leptin-sensitive hypothalamic neurons protected against the dietary induction of obesity. Therefore, this proposal hypothesizes that chronic overnutrition activates IKK&#946;/NF-&#954;B in the hypothalamus, desensitizes hypothalamic neurons to insulin and leptin, and causes energy imbalance leading to obesity-T2D. This hypothesis predicts that suppressing hypothalamic IKK&#946; could reverse these diseases. The 3 specific aims which will be pursued are as follows: (1) depict the effect of overnutrition on NF-&#954;B in the insulin/leptinsensitive MBH neurons; (2) study the role of IKK&#946;/NF-&#954;B on hypothalamic insulin and leptin resistance; (3) assess the metabolic outcomes of ablating IKK&#946; site-specifically in the MBH neurons or cell-specifically in the most relevant subtypes of insulin/leptin sensitive neurons AGRP and POMC neurons. To achieve these aims, a series of our established mouse models and approaches of site-directed gene manipulations will be empoyed to analyze NF-&#954;B, insulin/leptin signaling, and the metabolic phenotypes. The completion of this study will advance our knowledge about the brain pathogenesis of obesity-T2D, provide a molecular basis for developing new therapeutic and preventive strategies, and also establish a new model to study the nutritioninflammation axis in the brain underlying nutritional diseases.